Dr. Rabinovitch’s group has shown that the release of the transcription factor, AML1, from the nuclear matrix to the nuclear extract, is associated with increased elastase activity (Mitani Y et al. FASEB J 2001), a key event in the development of pulmonary vascular disease (Cowan K et al. Nature Medicine 2000). Work related to my PHA research proposal was first presented at the Arteriosclerosis Thrombosis Vascular Biology (ATVB) 6th Annual Conference in Washington, DC in April 2005. This was a platform session in which we showed the opposing effects of bone morphogenetic protein (BMP) and epidermal growth factor (EGF) in regulating transcriptionally active AML1 in human pulmonary artery smooth muscle cells (SMC): BMP-2 shuttles AML1 from the nuclear extract to the nuclear matrix where it is either non-transcriptionally active, or acts as a repressor of growth promoting genes. Loss of function mutations in the BMP-RII gene are common in idiopathic and familial forms of PAH, and our preliminary results suggest that this would lead to enhanced growth-promotive activity of AML1. This research project is still in progress: We are especially interested in the cross-talk between AML1, SMAD1, peroxisome proliferator-activated receptor gamma (PPARgamma) and wingless (Wnt) and related signaling downstream of BMP receptor II (BMP-RII).

Moreover, we have performed molecular and cell biology studies in which I first constructed a small hairpin RNAi pLentivirus to stably knock-down BMP-RII in human pulmonary artery smooth muscle cells (HPASMC). This receptor is mutated in pulmonary arterial hypertension leading to abnormal vascular cell proliferation and migration. I have since shown in HPASMC that BMP-2 signals through BMP-RII, and further demonstrated that there is rapid nuclear translocation and DNA binding of PPARgamma in response to BMP-2 stimulation. This is important because PPARgamma suppresses smooth muscle cell proliferation and BMP-2 signals through BMP-RII. We are currently investigating whether loss of PPARgamma activity directly leads to disturbed gene regulation downstream of BMP-RII signaling in the pulmonary circulation (for PASMC: see Journal of Clinical Investigation 2008; 118: 1846-1857).

We also carried out whole animal studies in apoE deficient mice (apoE -/-) and thereby established a novel mouse model for pulmonary arterial hypertension (PAH) associated with insulin resistance. Strikingly, oral treatment with an insulin-sensitizing PPARgamma agonist led to complete regression of PAH (i.e. regression of increased right ventricular systolic pressure as an indicator of PA pressure, right ventricular hypertrophy and peripheral pulmonary arterial muscularization) in insulin-resistant apoE -/- mice (see Circulation 2007; 115: 1275-1284). In collaboration with Dr. Roham T. Zamanian and colleagues, we then demonstrated that insulin resistance is more prevalent in 81 women with PAH (mean age 49.1±19.3 yrs) than in the general population, and may be a novel risk factor or disease modifier that might impact on survival (European Respiratory Journal 2009; 33: 318-324 epub 12/2008). Taken together, we suggest that PPARgamma agonists might reverse SMC proliferation and vascular remodeling in insulin-sensitive and insulin-resistant PAH patients with or without BMP-RII dysfunction.

For optimal viewing of PHAssociation.org, please use a standards-compliant browser such as Google Chrome or Firefox.

The information provided on the PHA website is provided for general information only. It is not intended as legal, medical or other professional advice, and should not be relied upon as a substitute for consultations with qualified professionals who are familiar with your individual needs.